Excretion of aminoglycosides in a rat kidney model.

Dactimicin is a new aminoglycoside antibiotic with an interesting low nephrotoxicity in animal experimental models. In order to establish if a correlation exists between the nephrotoxic effect and renal pharmacokinetic behaviour of aminoglycosides, tobramycin, sisomicin and dactimicin were studied in a model of isolated and perfused rat kidney. Concentrations in venous and urinary effluent during a continuous perfusion of a constant concentration of drugs were evaluated. The influence of active transport was studied comparing excretion data obtained with perfusion buffer with or without glucose. In the present experimental model the renal excretions of the aminoglycosides tested are quite similar and cannot account for the different nephrotoxicity observed in animals.

The single-dose pharmacokinetics of 5-epi-sisomicin (Sch 22591) in human volunteers.

5-epi-sisomicin was given as a single 1 mg/kg intramuscular injection to six adult male volunteers. No adverse effects were observed and the pharmacology was very similar to that of sisomicin. The extended spectrum of 5-epi-sisomicin and its enhanced antipseudomonal activity prompt further clinical evaluation of this agent.

[Graphic method of assessing the maximum cumulative excretion of a drug]. / Graficheskii sposob otsenki maksimal'noi kumuliativnoi ékskretsii lekarstvennogo sredstva.

Inaccuracy in estimation of the maximum excretion of drugs (M infinity e) is the main cause of errors in determination of their pharmacokinetic parameters by the data of the cumulative excretion (Me(t)). It was shown that the M infinity e value could be determined analytically with the following equation: (formula; see text) where S0Me leads to t is the area under the cumulative excretion curve and ke1 is the elimination constant. The equation was derived from integration of the equation of the cumulative excretion of drugs, the pharmacokinetics of which could be formalized with the linear one-compartmental model. When the data were linearized on the coordinates S0Me leads to t/t - Me(t)/t, the M infinity e value was determined by the portion of the curve on the ordinate and the ke1 value was calculated by the negative reverse value of the regression coefficient. The advantage of the method is that collection of the excrete samples is not limited by the use of the method. The calculations may be performed with a calculator or manually. The possibilities of the method are illustrated with reference to an analysis of the simulated and experimental data.

[Pharmacokinetic prediction of the efficacy of using sisomicin in wound infections]. / Farmakokineticheskoe prognozirovanie éffektivnosti primeneniia sizomitsina pri ranevoi infektsii.

The pharmacokinetics of sisomicin in the blood, infection foci and urine of patients with wound infections was studied comparatively. Higher blood levels of the antibiotic after intravenous injection as compared to those after intramuscular injection provided its more intensive penetration into the tissues of the wound edges and bottom. After intravenous injection the sisomicin concentration in the tissues was sufficient for inhibition of the strains of Staphylococcus, E. coli and Ps. aeruginosa detected in the patients, while after intramuscular injection the antibiotic levels were sufficient only for inhibition of the first two causative agents. Comparison of the data on the sisomicin pharmacokinetics in the blood and tissues of the wounds provided the characteristics of the level of the drug penetration into the focus of the infection ("therapeutic availability"). Since the levels of sisomicin in the blood and infection foci were highly variable in different individuals. It is recommended that the antibiotic be used under the control of its concentrations in patients. It was shown that the data on the sisomicin renal excretion might be used for the purposes of the pharmacokinetic control.

[Pharmacokinetics of a cefotetan and an aminoglycoside preparation in combined administration. 2. Absorption and exercise of cefotetan and sisomicin in dogs when the two are given together].

Cefotetan (20 mg/kg i.v.) and sisomicin (10 mg/kg i.m.) were administered alone or in combination to Beagle dogs. The mean plasma concentrations of cefotetan administered in combination with sisomicin at the above dosages were 98.0 microgram/ml at 5 minutes, 45.7 microgram/ml at 30 minutes and 3.46 microgram/ml at 4 hours. These plasma concentrations of cefotetan were similar to those of cefotetan administered alone to the corresponding dogs. The calculated plasma half-lives (T 1/2 beta) of cefotetan were 53.9 minutes in combination with sisomicin and 57.4 minutes alone. The excretion of cefotetan in dog urine were 52.4% and 50.2% of the dose after administration in combination with sisomicin and alone, respectively, during 24 hours. The results indicate that there were no significant differences in the pharmacokinetics of cefotetan alone or in combination with sisomicin in dogs. The maximum concentrations of sisomicin in dogs administered in combination with cefotetan were 20.2 microgram/ml at 30 minutes after dosing. The concentrations of 11.7 microgram/ml at 2 hours and 3.13 microgram/ml at 4 hours of administration were maintained in plasma. The calculated plasma half-lives of sisomicin were 68.8 minutes in combination with cefotetan and 86.4 minutes alone. The urinary rcoveries of sisomicin were 79.3% and 76.1% in combination with cefotetan and alone, respectively, during 24 hours. There were no significant differences in the pharmacokinetics of sisomicin alone and in combination with cefotetan in dogs.

Antibiotic concentrations in the urine from kidneys of unequal function.

Little attention has been given to whether an effective concentration of an antibiotic is obtained in the urine of a patient without azotemia who has one poorly functioning kidney and a contralateral normal kidney. This study was undertaken to measure the concentration of various antibiotics in the urine from both kidneys of 20 patients with unilateral renal disease and a radiologically and functionally normal contralateral kidney. Prior to ureteric catheterization each patient received a single parenteral dose of an antibiotic. The peak urinary drug concentration from the damaged kidney per unit of its creatinine clearance exceeded that for the normal kidney for 11/13 patients treated with an aminoglycoside and 6/7 given a cephalosporin. The most severely damaged kidney had a creatinine clearance of 0.6 ml/min. This patient received sisomicin and the peak urinary concentration was only 1.8 micrograms/ml. If a damaged kidney has a creatinine clearance less than 10-15 ml/min it would seem more appropriate to use a cephalosporin rather than an aminoglycoside antibiotic.

Renal pharmacology of netilmicin.

Netilmicin (Sch 20569), a new semisynthetic aminoglycoside, was studied for its effects on kidney function and mechanisms by which it is handled by the kidneys. Measurements of glomerular filtration rate (GFR) and urinalysis in chronic rat studies indicated that the nephrotoxicity of netilmicin was remarkably less than that of gentamicin. Gentamicin caused a dose-related reduction in GFR in association with glucosuria and elevated fractional excretion of K(+). By contrast, high doses of netilmicin produced only slight reduction in GFR with increased fractional excretion of K(+) but without glucosuria. In separate experiments, rats were shown to excrete 71 to 90% of netilmicin or gentamicin in 24 h after daily intramuscular administration of doses of 20 or 40 mg/kg for 4 days. In acute experiments on anesthetized dogs, GFR and renal plasma flow were unaffected at serum levels of 11.0 +/- 0.6 mug/ml maintained by constant infusion of netilmicin for 5 h. The renal clearance of netilmicin was significantly correlated with GFR. The urinary output of netilmicin was 80.0 +/- 4.2% of the infusion rate and was independent of urine flow over the range of 0.04 to 0.33 ml/kg per min. Preferential accumulation of netilmicin occurred in the renal cortex; the cortex-serum and medulla-serum ratios were 9.9 +/- 1.2 and 4.2 +/- 0.6, respectively. In addition, the extraction ratio of netilmicin, which was lower than that of inulin, suggested that netilmicin reabsorption occurs in the proximal tubule and results in cortical accumulation. It is concluded that netilmicin, like gentamicin, is excreted by the dog kidney by glomerular filtration plus limited reabsorption. However, the new drug is characterized by low intrinsic nephrotoxicity in rats.